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Objectives We characterized the microbiota in systemic sclerosis (SSc), focusing on the skin-oral-gut axis and serum and faecal free fatty acid (FFA) profile. Methods Twenty-five SSc patients with ACA or anti-Scl70 autoantibodies were enrolled. The microbiota of faecal, saliva and superficial epidermal samples was assessed through next generation-sequencing analysis. Gas chromatography-mass spectroscopy was used to quantity faecal and serum FFAs. Gastrointestinal symptoms were investigated with UCLA GIT-2.0-questionnaire. Results The ACA+ and anti-Scl70+ groups displayed different cutaneous and faecal microbiota profiles. The classes of cutaneous Sphingobacteria and Alphaproteobacteria, the faecal phylum of Lentisphaerae, the classes of Lentisphaeria and Opitutae, and the genus of NA-Acidaminococcaceae were significantly higher in faecal samples of the ACA+, compared with anti-Scl70+ patients. The cutaneous Sphingobacteria and the faecal Lentisphaerae were significantly correlated (rho = 0.42; p= 0.03). A significant increase in faecal propionic acid was observed in ACA+ patients. Moreover, all faecal medium-chain FFAs and hexanoic acids were significantly higher in ACA+ compared with anti-Scl70+ group (p< 0.05 and p< 0.001, respectively). In the ACA+ group, the analysis of serum FFA levels showed an increasing trend in valeric acid. Conclusions Different microbiota signatures and FFA profiles were found in the two groups of patients. Despite being in different body districts, the cutaneous Sphingobacteria and faecal Lentisphaerae appear interdependent.

ObjectivesPleuroparenchymal fibroelastosis (PPFE) is characterized by predominantly upper lobe pleural and subjacent parenchymal fibrosis; PPFE features were described in patients with rheumatic autoimmune diseases (RAID). A systematic literature review was performed to investigate the prevalence, prognosis and potential association of PPFE with previous immunosuppression in RAID.MethodsEMBASE, Web of Science and PubMed databases were questioned from inception to 1 September 2019. Articles published in English and addressing PPFE in patients with RAID were selected.ResultsTwenty out of 794 papers were selected with a total of 76 cases of RAID-PPFE patients (20 SSc, 9 RA, 6 IIM6 primary SS, 5 overlap syndromes, 3 ANCA-associated vasculitides, 2 granulomatosis with polyangiitis, 1 microscopic polyangiitis, 1 UCTD, 1 SLE, 1 GCA and 21 patients with non-specified RAID). Dyspnoea was the most frequently reported symptom (37/48 patients, 77%). Patients frequently presented with a restrictive pattern and decline in diffusing lung capacity for carbon monoxide. During the follow-up, 7/12 patients had progression at imaging, 22/39 presented a generic clinical worsening, 19/38 had a functional deterioration and 15/43 remained stable.ConclusionThe present systematic literature review confirms that PPFE features are present in RAID. Rheumatologists should be aware of this new radiological pattern that holds a bad prognosis.

Objectives Cardiac rhythm disturbances constitute the most frequent cardiovascular cause of death in SSc. However, electrocardiographic findings are not a part of risk stratification in SSc. We aimed to translate 24 h Holter findings into a tangible risk prediction score using cardiovascular magnetic resonance. Methods The Scleroderma Arrhythmia Clinical Utility Study (SAnCtUS) was a prospective multicentre study including 150 consecutive SSc patients from eight European centres, assessed with 24 h Holter and cardiovascular magnetic resonance, including ventricular function, oedema (T2 ratio) and late gadolinium enhancement (%LGE). Laboratory/clinical parameters were included in multivariable corrections. A combined endpoint of sustained ventricular tachycardia requiring hospitalization and sudden cardiac death at a median (interquartile range) follow-up of 1 (1.0–1.4) year was generated. Results Only T2 ratio and %LGE were significant predictors of ventricular rhythm disturbances, but not of supraventricular rhythm disturbances, after multivariable correction and adjustment for multiple comparisons. Using decision-tree analysis, we created the SAnCtUS score, a four-category scoring system based on T2 ratio and %LGE, for identifying SSc patients at high risk of experiencing ventricular rhythm disturbance at baseline. Increasing SAnCtUS scores were associated with a greater disease and arrhythmic burden. All cases of non-sustained ventricular tachycardia (n = 7) occurred in patients with the highest SAnCtUS score (=4). Having a score of 4 conveyed a higher risk of reaching the combined endpoint in multivariable Cox regression compared with scores 1/2/3 [hazard ratio (95% CI): 3.86 (1.14, 13.04), P = 0.029] independently of left ventricular ejection fraction and baseline ventricular tachycardia occurrence. Conclusion T2 ratio and %LGE had the greatest utility as independent predictors of rhythm disturbances in SSc patients.

Background Malignant arrhythmias due to cardiac involvement are a frequent cause of death in systemic sclerosis (SSc). Cardiac involvement, which is linked to both ischaemic and non-ischaemic fibrotic deposition, is often subclinical. Cardiovascular magnetic resonance (CMR) is the non-invasive gold standard for myocardial tissue characterization and can detect macroscopic myocardial fibrosis through late Gadolinium enhancement (LGE). Aim To evaluate the role of LGE to predict malignant arrhythmias requiring implantable cardioverter defibrillator (ICD) in SSc. Methods 289 SSc patients underwent a thorough clinical evaluation and CMR exam using a 1.5 T scanner. Biventricular function parameter by SSFP cine images, oedema by STIR T2 images, and macroscopic fibrosis by LGE were assessed. Patients were followed-up and malignant ventricular arrhythmias requiring ICD implantation was considered as event. Results Out of 289 patients, 111 (38.4%) showed LGE and 83/111 (28.7% of the total population) showed a non-junctional distribution. During the follow-up (45±27 months), 10 patients needed ICD after malignant ventricular arrhythmias (7 patients with LGE, 3 patients without LGE). CMR predictors of cardiac events by univariate analysis were left and right ventricular ejection fractions, indexed right atrial area and non-junctional LGE. At multivariate analysis, macroscopic myocardial fibrosis detected by LGE was an independent predictor (hazard ratio 5.4; 95% C.I. 1.1–28.8, p Conclusions Presence of ventricular LGE at CMR may represent an independent predictor for further malignant ventricular arrhythmias requiring ICD implantation in SSc patients. Kaplan-Meier curves Funding Acknowledgement Type of funding source: None

Objective. Dysfunctional angiogenesis is a pathogenetic marker of SSc. Circulating levels of endothelial progenitor cells are reduced, and mesenchymal stromal cells show a reduced differentiation into endothelial cells and capacity to form capillaries. This suggests that pathophysiologically relevant changes may already exist in SSc bone marrow (BM) stromal cells that may affect downstream angiogenesis. The aim of this study is to evaluate, in SSc BM, angiogenesis, cellular immune system and fibrosis. Methods. Eight SSc patients affected by a severe dcSSc and screened for autologous haematopoietic stem cells transplantation (HSCT) underwent a BM biopsy. BM biopsies were compared with six healthy controls. To evaluate angiogenesis and cellular immunity, the following antibodies were used: vascular endothelial growth factor (VEGF), kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/flk-1), MMP-9 and CD34. To evaluate fibrosis, silver impregnation for reticulum was used. The number of vessels, the mean area of vascularization, the perimeter and microvessel density (MVD) were measured with a multiparametric computerized imaging analysis. Results. A significant reduction in BM vascularity was found, while VEGF expression was much higher in SSc BM samples. Two patients had a Grade 2, whereas another two had a Grade 1 fibrosis. Conclusion. In SSc, BM is characterized by a reduction of microvascular density and number of vessels and a significant increase of VEGF. This indicates that BM may be involved in the process of loss of angiogenesis, despite the presence of high local and systemic levels of VEGF.

Systemic sclerosis (SSc) is characterized by microvascular and macrovascular alterations. The D allele of the ACE I/D polymorphism is known to be associated with an increased incidence of atherosclerosis and has been recently proposed as associated with increased risk of SSc. This study evaluates the relationship between intima-media thickness (IMT), ankle-brachial pressure measurements (ABPI) and ACE I/D polymorphism in SSc patients.According to the presence of ACE D allele (analysed by PCR), 53 SSc patients (47 females and 6 males; median age was 60.4 +/- 10.68 yrs; range 40-75 yrs) were divided in carriers of the D allele (DD + ID) (n = 46) and carriers of the I allele (II) (n = 7). In these patients, IMT and ABPI [calculated as the posterior tibial artery pressure (mmHg) divided by the brachial pressure] were obtained. Forty-three healthy controls (40 women and 13 men; median age 56.3 +/- 10.23; range 40-70 yrs) of the same ethnicity were recruited.SSc patients had IMT significantly higher than controls (0.85 +/- 0.03 vs 0. 68 +/- 0.01; P0.03). No significant differences (P0.3) in ABPI values between patients (1.018 +/- 0.10) and controls (1.091 +/- 0.11) were found. SSc patients with ACE DD and ID genotype showed an IMT significantly greater (0.89 +/- 0.03) than those carrying the II genotype (0.61 +/- 0.01) (P0.04). ABPI was not different among ACE gene genotypes.Our findings confirm an increased prevalence of macrovascular disease in SSc patients and show that IMT is greater in patients carrying the ACE DD and ID genotype in comparison with II homozygotes. This suggests that, in SSc, the presence of ACE D allele may predispose to an involvement of the macrovascular system.